Cytotoxic CD8<sup>+</sup> T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons.

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License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_C20819493CBC
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Cytotoxic CD8<sup>+</sup> T lymphocytes expressing ALS-causing SOD1 mutant selectively trigger death of spinal motoneurons.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Coque E., Salsac C., Espinosa-Carrasco G., Varga B., Degauque N., Cadoux M., Crabé R., Virenque A., Soulard C., Fierle J.K., Brodovitch A., Libralato M., Végh A.G., Venteo S., Scamps F., Boucraut J., Laplaud D., Hernandez J., Gergely C., Vincent T., Raoul C.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
05/02/2019
Peer-reviewed
Oui
Volume
116
Number
6
Pages
2312-2317
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Adaptive immune response is part of the dynamic changes that accompany motoneuron loss in amyotrophic lateral sclerosis (ALS). CD4 <sup>+</sup> T cells that regulate a protective immunity during the neurodegenerative process have received the most attention. CD8 <sup>+</sup> T cells are also observed in the spinal cord of patients and ALS mice although their contribution to the disease still remains elusive. Here, we found that activated CD8 <sup>+</sup> T lymphocytes infiltrate the central nervous system (CNS) of a mouse model of ALS at the symptomatic stage. Selective ablation of CD8 <sup>+</sup> T cells in mice expressing the ALS-associated superoxide dismutase-1 (SOD1) <sup>G93A</sup> mutant decreased spinal motoneuron loss. Using motoneuron-CD8 <sup>+</sup> T cell coculture systems, we found that mutant SOD1-expressing CD8 <sup>+</sup> T lymphocytes selectively kill motoneurons. This cytotoxicity activity requires the recognition of the peptide-MHC-I complex (where MHC-I represents major histocompatibility complex class I). Measurement of interaction strength by atomic force microscopy-based single-cell force spectroscopy demonstrated a specific MHC-I-dependent interaction between motoneuron and SOD1 <sup>
G93A
</sup> CD8 <sup>+</sup> T cells. Activated mutant SOD1 CD8 <sup>+</sup> T cells produce interferon-γ, which elicits the expression of the MHC-I complex in motoneurons and exerts their cytotoxic function through Fas and granzyme pathways. In addition, analysis of the clonal diversity of CD8 <sup>+</sup> T cells in the periphery and CNS of ALS mice identified an antigen-restricted repertoire of their T cell receptor in the CNS. Our results suggest that self-directed immune response takes place during the course of the disease, contributing to the selective elimination of a subset of motoneurons in ALS.
Keywords
Amyotrophic Lateral Sclerosis/diagnosis, Amyotrophic Lateral Sclerosis/genetics, Amyotrophic Lateral Sclerosis/metabolism, Amyotrophic Lateral Sclerosis/physiopathology, Animals, Cell Communication/immunology, Cell Death, Cell Survival/genetics, Disease Models, Animal, Gene Expression, Granzymes/metabolism, Histocompatibility Antigens Class I/immunology, Lymphocyte Activation/immunology, Mice, Mice, Transgenic, Motor Neurons/immunology, Motor Neurons/metabolism, Mutation, Phenotype, Severity of Illness Index, Spinal Cord/cytology, Superoxide Dismutase-1/genetics, T-Lymphocytes, Cytotoxic/immunology, T-Lymphocytes, Cytotoxic/metabolism, fas Receptor/metabolism, amyotrophic lateral sclerosis, cytotoxic T lymphocytes, major histocompatibility complex I, motoneuron, neuroimmunity
Pubmed
Web of science
Open Access
Yes
Create date
01/03/2019 12:43
Last modification date
20/08/2019 15:37
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